Chung et al. SpringerPlus (2016) 5:271 DOI 10.1186/s40064-016-1890-5

SHORT REPORT

Synthesis of hexahydrofuro[3,2-c]quinoline, a martinelline type analogue and investigation of its biological activityP.‑Y. Chung1, J. C.‑O. Tang1, C.‑H. Cheng1, Z.‑X. Bian2, W.‑Y. Wong3, K.‑H. Lam1* and C.‑H. Chui1,2*

Abstract

Background: Candida susceptibility commonly occurs in breast cancer patients. Of which, Candida albicans is considered as a common pathogen causing candidiasis. Martinella iquitosensis (Bignoniaceae) is one of the species belonged to Martinella, distributed widely in Amazon basin. Its root extract yielded two complex substituted tetrahy‑droquinolines, Martinelline and Martinellic acid which were the first natural non‑peptide bradykinin receptor antago‑nists identified.

Findings: In this study, a novel martinelline type analogue, named 2,3,3a,4,5,9b‑hexahydro‑8‑phenoxy‑4‑(pyridin‑2‑yl)furo[3,2‑c]quinoline, was synthesized and its preliminary anticancer activity and antifungal potential were investigated. This compound showed potential anticancer activity against MDAMB‑231 breast cancer cells. Meanwhile it could enhance the fungistatic activity of miconazole against Candida albicans.

Conclusions: These findings provide an implication for the continue investigation and development of martinelline type analogues as therapeutic agents in the future.

Keywords: Biological activity, Candida albicans, Hexahydrofuro[3,2‑c]quinoline, Martinelline type analogue

© 2016 Chung et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

BackgroundBreast cancer patients are commonly susceptible to can-didiasis. Candida albicans (C. albicans) is one of the opportunistic fungi especially observed in immunocom-promised patients (Calderone and Fonzi 2001), such as cancer patients. Previous studies have investigated the prevalence of candidiasis in cancer patients. Among 845 women with multiple lymph node positive or metastatic breast carcinoma receiving high-dose chemotherapy and autologous bone marrow transplantation at Duke Uni-versity Medical Center during 1992–1997, 29 of them (3.4  %) developed candidemia. Of which, 23  % of them were found to be infected with C. albicans. The mortal-ity was highest for the women who were infected by C.

albicans (71  %) (Gottfredsson et  al. 2003). In 2005, 400 adult patients with the hematological malignancy, head neck or solid tumor (including breast cancer) were recruited randomly into the study on admission to the regional cancer center of the Norfolk and Norwich Uni-versity Hospital. There were 56.8  % (227 of 400) of all cancer patients and 18.9 % (43 of 227) of those who had clinical and microbiological evidence of oral candidiasis. Among 269 yeast isolates recovered from 227 patients, C. albicans was the most common yeast (74 %) causing colonization and infection (Schelenz et al. 2011).

Martinella can be used as indigenous medicine for eye disease caused by bacteria in various ethnolinguis-tic groups of some South American countries (Witherup et  al. 1995). Martinella iquitosensis (Bignoniaceae), one of the species belonged to Martinella, is a tropical plant with dark purple corolla in South American and distrib-uted widely in Amazon basin (Zuntini and Lohmann 2014). Its root extract yielded two complex substituted tetrahydroquinolines, Martinelline and Martinellic

Open Access

*Correspondence: kim.hung.lam@polyu.edu.hk; chchui@hkbu.edu.hk 1 State Key Laboratory of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China2 Clinical Division, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, ChinaFull list of author information is available at the end of the article

Page 2 of 6Chung et al. SpringerPlus (2016) 5:271

acid (Fig.  1a) which were the first natural non-peptide bradykinin receptor antagonists identified by Witherup et  al. (1995). Afterwards, the studies on the synthesis of new compounds with this interesting core have been increased. For instance, hexahydro-2H-pyrano[3,2-c]quinolines were found to be a potent agent against patho-genic gram-negative bacteria and Magesh et  al. discov-ered that one of the synthesized compounds exhibits good bacteriolytic activity against Virbio vulnificus and Vibrio parahaemolticus (Magesh et  al. 2004). Another research group (Kantevari et  al. 2011) also synthesized a series of hexahydro-2H-pyrano[3,2-c]quinolines and studied their activity against the Mycobacrtium tuber-culosis H37Rv. Three of the synthesized compounds showed a comparable activity as ethambutol. In addition, it was reported that hexahydro-2H-pyrano[3,2-c]quino-lines could be used as selective σ1 receptor ligand for the treatment of pain (Diaz et al. 2013).

Heterocyclic compounds are important candidates in the development of new class of structural entities for medicinal applications. Quinoline is a heterocyclic aro-matic nitrogen containing compound characterized by a double-ring structure that has a benzene ring fused to pyridine at two adjacent carbon atoms (Keri and Patil 2014). Among these structures, tetrahydroquinoline derivatives demonstrated extensive biological activi-ties. They included anticancer (Subramanian et al. 2011), antioxidant (Dorey et  al. 2000) and antifungal (Vargas Méndez et  al. 2010) activity. The construction and ste-reochemistry of the tricyclic ring system have also been recently reported (Calleja et  al. 2014). In the previous years, we have prepared and studied some simple 2-sub-situted terahydroquinoline alkaloid analogues as anti-tumor agents possessing notable cytotoxicity towards

human Hep3B heptocellular carcinoma cells (Lam et al. 2013). In addition, we have reported the antimicrobial activity of some novel synthesized quinoline analogues (Lam et al. 2014; Chung et al. 2015). Inspired by unique core moiety of Martinelline and the reported promis-ing bioactivity of tetrahydroquinolines and their related natural product analogues, we have designed compound 1 (Fig. 1b) and its potential biological activity was tested on MDAMB-231 breast cancer cells and C. albicans.

Strategically, we aimed to develop a simple and mild reaction pathway for the synthesis of compound 1 using one-pot multicomponent reaction with substituted ani-line, aldehyde and alkene. Various catalysts, such as NbCl5 (da Silva et al. 2014), Fe2(SO4)·xH2O (Khan et al. 2011; Das et  al. 2014), In(OTf)3 (Priestley et  al. 2013) and BiCl3 (Kouznetsov et  al. 2011) were reported to be effective for this reaction. Particularly, bismuth and its compounds are recognized as safe and green Lewis acid catalysts (Leonard et  al. 2002; Mohan 2010). With increasing concern on the advancement of “green reac-tion” in last decade, the application of bismuth(III) com-pounds and their important roles in organic synthesis have been clearly addressed in recent researches (Gas-pard-Iloughmane and Le Roux 2004; Bothwell et al. 2011; Ollevier 2013). Herein, we report a bismuth(III)-cata-lyzed synthesis of substituted tetrahydroquionlines.

MethodsGeneral procedure for the synthesis of 2,3,3a,4,5,9b‑hexahydro‑8‑phenoxy‑4‑(pyridin‑2‑yl)furo[3,2‑c]quinoline (compound 1)All reagents were purchased from Sigma-Aldrich. All the synthesized compounds were characterized by 1H NMR, 13C NMR, mass spectrometry and X-ray crystallography.

Fig. 1 Structure of a Martinellic acid and Martinelline; b compound 1; c MOLECULAR structure of compound 1

Page 3 of 6Chung et al. SpringerPlus (2016) 5:271

NMR spectra were recorded on a Bruker DPX400 Fou-rier transform spectrometer using CDCl3 as solvent unless otherwise specified. X-ray crystallographic analy-sis was performed by Bruker D8_VENTURE PHOTON 100. To a mixture of 2-Pyridinecarboxaldehyde (1.0 mol equiv) and 4-Phenoxyaniline (1.2  mol equiv) was added in solvent (2  mL) and stirred. Catalyst (0.2  mol equiv) and 2,3-Dihydrofuran (1.2  mol equiv) were then added. The reaction mixture was stirred at room temperature for 1.5 h. Solvent was then removed and the residue was extracted with dichloromethane. The organic layer was washed with 10 % Na2CO3 solution and water. Dried over anhydrous Na2SO4 and removed the solvent by rotary evaporator. The crude product was purified by silica gel column chromatography.

Synthesis and characterization of compound 11H NMR (400 MHz, CDCl3): δ 1.55–1.57 (m, 1H), 2.03–2.09 (m, 1H), 3.07–3.14 (m, 1H), 3.76–3.80 (m, 2H), 4.53 (s, 1H), 4.83 (d, 1H, J = 2.8 Hz), 5.30 (d, 1H, J = 8.0 Hz), 6.70 (d, 1H, J = 8.8 Hz), 6.84–6.98 (m, 1H), 7.00–7.06 (m, 3H), 7.11 (d, 1H, J = 2.4 Hz), 7.25–7.27 (m, 1H), 7.31–7.33 (m, 2H), 7.50 (d, 1H, J = 8.0 Hz), 7.75–7.77 (m, 1H), 8.64 (d, 1H, J = 4.4 Hz); 13C NMR (100 MHz, CDCl3): δ 24.40, 43.33, 57.67, 66.62, 75.91, 116.17, 117.60, 120.43, 120.56, 120.98, 122.18, 122.42, 123.85, 129.53, 136.79, 140.93, 149.10, 149.16, 158.66, 160.13; HRMS (ESI): Calcd. for C22H21N2O2 [M + H]+, 345.1598. found 345.1597. Melt-ing point = 132.4–134.2 °C. Optimized yield = 26.8 %.

[3‑(4,5‑dimethylthiazol‑2‑yl)‑5‑(3‑carboxymethoxyphenyl) ‑2‑(4‑sulfophenyl)‑2H‑tetrazolium] (MTS) assay and cellular morphologyMDAMB-231 cells were obtained from American Type of Culture Collection. Changes in the cellular viability of compound 1-treated cells were monitored using the MTS activity assay (20). Briefly, MDAMB-231 breast carcinoma cells were seeded at day 0. After 24 h, complete medium was changed and compound 1 was added at different con-centrations (starting with 50 µM containing 0.1 % dime-thyl sulfoxide (DMSO) as vehicle). Doxorubicin at 8 µM was used as a positive control. After 48 h of incubation, incubation medium was removed and fresh medium with MTS (Promega)/phenazine methosulfate as electron coupling agent mixed solution was added. Lastly, optical absorbance was determined at 490  nm using a micro-plate reader (Perkin Elmer Victor V) according to the user manual. Additionally, any morphological changes asso-ciated with compound 1 and doxorubicin treated breast cancer cells were recorded under an inverted microscope after fixing the cells with trichloroacetic acid and cellu-lar protein was stained with sulforhodamine B after 24 h (Kok et al. 2007; Lam et al. 2015a, b).

Determination of minimum inhibitory concentration (MIC) and sensitization assayCandida albicans was obtained from American Type of Culture Collection. The MIC values of synthesized com-pound 1 and miconazole nitrate were determined by the broth dilution method. Various concentrations of com-pound 1 and miconazole were loaded from a starting concentration of 50  µM containing 0.1  % dimethyl sul-foxide (DMSO) as vehicle and they were diluted serially. DMSO (0.1 %) was used as a vehicle control. The fungal samples were then incubated at 37 °C for 48 h. The mini-mum concentrations of compound 1 and miconazole that induced a complete growth inhibition would be deter-mined as their MIC values. For sensitization study, with compound 1 at 50 µM, miconazole was added at a start-ing concentration of 1.56, 0.78 and 0.39 µM respectively. After incubation, the fungal samples were treated with MTS/PMS as above (Lam et al. 2015a).

Results and discussionSynthesis of compound 1We first screened different metal salts as catalyst for this reaction (Table 1). It was found that only metal(III) salts (Table 1, Entry 5–7) gave our desired compound 1 and, in particular, bismuth(III) nitrate pentahydrate provided the highest yield among all the selected catalysts. With such preliminary screening, we used Bi(NO3)3·5H2O as catalyst for further optimization of the reaction under various conditions aiming to enhance the product yield (Table 2). It is noted that addition of catalyst in 0.2 mol equivalent and the reaction carried in ethanol (Table  2, Entry 7) provided the best yield. With the present work, further investigation is ongoing to develop a greener and more effective reaction for the synthesis of compound 1.

Anticancer activity of compound 1Compound 1 at 50 µM (~17 µg/ml) could readily induce cell death on MDAMB-231 cells with significant cel-lular morphological changes when compared with the untreated control (Fig.  2a) such as cell rounding and shrinkage (Fig. 2b) which were similar to those from the positive reference, doxorubicin (Fig.  2c) at 8  µM after 24 h. As shown in Fig. 2d, a dose dependent cytotoxicity of compound 1 on MDAMB-231 breast cancer cells was observed after a 48 h of incubation.

MIC of compound 1The MIC value of miconazole on C. albicans was found to be 3 µM. Compound 1, however, did not exhibit anti-fungal activity on C. albicans of up to 50 µM. However, we found that compound 1 could enhance the antifun-gal activity of miconazole on C. albicans. In the sub-sequent tests, compound 1 was added simultaneously

Page 4 of 6Chung et al. SpringerPlus (2016) 5:271

with different concentrations of miconazole. As shown in Fig.  3, compound 1 could significantly potentiate the antifungal action of miconazole. Recently, we have shown that corilagin could sensitize Hep3B hepatoma cells to

cisplatin and doxorubicin (Gambari et al. 2014). Here we suggest that compound 1 at 50  µM could significantly improve the fungistatic property of miconazole against C. albicans.

Table 1 Catalyst screening to optimize the product yield

All the reactions were carried out at room temperature in acetonitrile (ACN) for 1.5 h

N.D. not detected

Entry Catalyst Yield (%)

1 MnCl2·4H2O N.D.

2 FeSO4·7H2O N.D.

3 CoCl2·6H2O N.D.

4 CuSO4·5H2O N.D.

5 Fe(NO3)3·9H2O 16.5

6 BiCl3 9.9

7 Bi(NO3)3·5H2O 19.6

Table 2 Optimization on the product yield using Bi(NO3)3·5H2O

All the reactions were carried out at room temperature and catalyst (0.2 mol equiv) was addeda Catalyst (0.05 mol equiv) was addedb Catalyst (0.1 mol equiv) was addedc 0.1 M nitric acid was used and no metal catalyst was addedd The reaction was carried out under reflux

Entry Solvent Reaction time (h) Yield (%)

1a ACN 1.5 6.8

2b ACN 1.5 10.2

3 ACN 1.5 19.6

4 CH2Cl2 1.5 17.1

5 Water 1.5 9.1

6c Water 1.5 12.0

7 Ethanol 1.5 22.2

8d ACN 1.5 21.8

9 Ethanol 0.5 26.8

10 Ethanol 3 25.3

11 Ethanol 7 18.6

Page 5 of 6Chung et al. SpringerPlus (2016) 5:271

ConclusionsIn this work, the synthesis and preliminary in  vitro bio-logical application of a novel martinelline type analogue, named 2,3,3a,4,5,9b-hexahydro-8-phenoxy-4-(pyridin-2-yl)furo[3,2-c]quinoline, were described. Interestingly, this

compound showed potential anticancer activity against MDAMB-231 breast cancer cells and it could simultane-ously potentiate the fungistatic activity of miconazole against a common human pathogenic fungus, C. albicans. As the obtained compound 1 consists of three chiral cen-tres, there should be eight stereoisomers exist. Further work will be carried out to isolate each isomer and inves-tigate their individual potential biological activity in order to elucidate if chirality is important in this group of com-pounds from the pharmaceutical point of view.

AbbreviationsC. albicans: Candida albicans; DMSO: dimethyl sulfoxide; MIC: mini‑mum inhibitory concentration; MTS: [3‑(4,5‑dimethylthiazol‑2‑yl)‑5‑(3‑carboxymethoxyphenyl)‑2‑(4‑sulfophenyl)‑2H‑tetrazolium].

Authors’ contributionsPYC carried out the chemistry experiments and drafted the manuscript. JCO participated in the chemistry experiments. CHC participated in the antifungal test. ZXB participated in the anticancer study. WYW participated in the chem‑istry experiments. KHL conceived of the study, participated in the design of the study and carried out the chemistry experiments. CHC conceived of the study, and participated in its design of the study, carried out the anticancer and antifungal studies and helped to draft the manuscript. All authors read and approved the final manuscript.

Fig. 2 a–c Cellular morphology of MDAMB‑231 cells after 24 h: a Untreated control; b compound 1 at 50 µM; c Doxorubicin at 8 µM as positive ref‑erence; and d MTS activity assay to determine the effect of compound 1 on MDAMB‑231 cells after 48 h. Reported results represent the mean ± SD from triplicate tests. This figure shows a representative experiment taken from three independent experiments giving similar results

Fig. 3 MTS activity assay to determine the effect of miconazole alone and micronazole with compound 1 (50 µM) on C. albicans. Reported results represent the mean ± SD from triplicate tests. This figure shows a representative experiment taken from three independent experiments giving similar results

Page 6 of 6Chung et al. SpringerPlus (2016) 5:271

Author details1 State Key Laboratory of Chirosciences, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China. 2 Clinical Division, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. 3 Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.

AcknowledgementsThis study has been supported by a grant from the Innovation Technology Commission to Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University and the research grants from Research Office of Hong Kong Baptist University (FRG1/14‑15/004, FRG1/14‑15/021, FRG1/14‑15/078, 38‑40‑116 and 03‑16‑176). We would like to thank the sup‑port from Prof. Zhou Zhongyuan for the X‑ray crystallography.

Competing interestsThe authors declare that they have no competing interests.

Received: 25 November 2015 Accepted: 17 February 2016

ReferencesBothwell JM, Krabbe SW, Mohan RS (2011) Applications of bismuth(III) com‑

pounds in organic synthesis. Chem Soc Rev 40(9):4649–4707Calderone RA, Fonzi WA (2001) Virulence factors of Candida albicans. Trends

Microbiol 9:327–335Calleja J, González‑Pérez AB, de Lera ÁR, Álvarez R, Fañanás FJ, Rodríguez F

(2014) Enantioselective synthesis of hexahydrofuro[3,2‑c] quinolines through a multicatalytic and multicomponent process. A new “aromatic sandwich” model for BINOL‑phosphoric acid catalyzed reactions. Chem Sci 5:996–1007

Chung PY, Gambari R, Chen YX, Cheng CH, Bian ZX, Chan ASC, Tang JCO, Leung PHM, Chui CH, Lam KH (2015) Development of 8‑benzyloxy‑sub‑stituted quinoline ethers and evaluation of their antimicrobial activities. Med Chem Res 24:1568–1577

da Silva BHST, Marana NL, Mafud AC, da Silva‑Filho LC (2014) A theoretical and experimental study to unequivocal structural assignment of tetrahydro‑quinoline derivatives. Struct Chem 25:327–337

Das DK, Sarkar S, Khan AT, Saravanan P, Patra S (2014) Synthesis of fused tetrahydropyrido[2,3‑c]coumarin derivatives as potential inhibitors for dopamine d3 receptors, catalyzed by hydrated ferric sulfate. RSC Adv 4:3581–3590

Diaz JL, Christmann U, Fernandez A, Luengo M, Bordas M, Enrech R, Carro M, Pascual R, Burgueno J, Merlos M, Benet‑Buchholz J, Ceron‑Bertran J, Ramirez J, Reinoso RF, Fernandez de Henestrosa AR, Vela JM, Almansa C (2013) Synthesis and biological evaluation of a new series of hexahydro‑2H‑pyrano[3,2‑c]quinolines as novel selective sigma1 receptor ligands. J Med Chem 56:3656–3665

Dorey G, Lockhart B, Lestage P, Casara P (2000) New quinolinic derivatives as centrally active antioxidants. Bioorg Med Chem Lett 10:935–939

Gambari R, Hau DKP, Wong WY, Chui CH (2014) Sensitization of Hep3B hepatoma cells to cisplatin and doxorubicin by corilagin. Phytother Res 28:781–783

Gaspard‑Iloughmane H, Le Roux C (2004) Bismuth(III) triflate in organic synthe‑sis. Eur J Org Chem 2004(12):2517–2532

Gottfredsson M, Vredenburgh JJ, Xu J, Schell WA, Perfect JR (2003) Candidemia in women with breast carcinoma treated with high‑dose chemotherapy and autologous bone marrow transplantation. Cancer 98:24–30

Kantevari S, Yempala T, Surineni G, Sridhar B, Yogeeswari P, Sriram D (2011) Synthesis and antitubercular evaluation of novel dibenzo[b, d]furan and 9‑methyl‑9H‑carbazole derived hexahydro‑2H‑pyrano[3,2‑c]quinolines via Povarov reaction. Eur J Med Chem 46:4827–4833

Keri RS, Patil SA (2014) Quinoline: a promising antitubercular target. Biomed Pharmacother 68:1161–1175

Khan AT, Das DK, Khan MM (2011) Ferric sulfate [Fe2(SO4)3·xH2O]: an efficient heterogeneous catalyst for the synthesis of tetrahydroquinoline deriva‑tives using Povarov reaction. Tetrahedron Lett 52:4539–4542

Kok SHL, Gambari R, Chui CH, Lau FY, Cheng GYM, Lai PBS, Lam WS, Chan ASC, Cheng CH, Teo ITN, Yu MWY, Tang JCO, Cheung F, Wong RSM (2007) Paradoxical proliferative potential of iron(II) sulphate on cancer cells after the 3‑(4,5‑dimethylthiazol‑2‑yl)‑5‑(3‑carboxymethoxyphenyl)‑2‑(4‑sulfophenyl)‑2H‑tetrazolium (MTS) assay. Int J Mol Med 19:971–975

Kouznetsov VV, Gomez CM, Parada LK, Bermudez JH, Mendez LY, Acevedo AM (2011) Efficient synthesis and free‑radical scavenging capacity of new 2,4‑substituted tetrahydroquinolines prepared via BiCl(3)‑catalyzed three‑component Povarov reaction, using N‑vinylamides. Mol Divers 15:1007–1016

Lam KH, Lee KKH, Gambari R, Wong RSM, Cheng GYM, Tong SW, Chan KW, Lau FY, Lai PBS, Wong WY, Chan ASC, Kok SHL, Tang JCO, Chui CH (2013) Preparation of Galipea officinalis Hancock type tetrahydroquinoline alka‑loid analogues as anti‑tumour agents. Phytomedicine 20:166–171

Lam KH, Gambari R, Lee KKH, Chen YX, Kok SHL, Wong RSM, Lau FY, Cheng CH, Wong WY, Bian ZX, Chan ASC, Tang JCO, Chui CH (2014) Preparation of 8‑hydroxyquinoline derivatives as potential antibiotics against Staphylo-coccus aureus. Bioorg Med Chem Lett 24:367–370

Lam PL, Gambari R, Kok SHL, Lam KH, Tang JCO, Bian ZX, Lee KKH, Chui CH (2015a) Non‑toxic agarose/gelatin‑based microencapsulation sys‑tem containing gallic acid for antifungal application. Int J Mol Med 35:503–510

Lam PL, Kok SHL, Gambari R, Kok TW, Leung HY, Choi KL, Wong CS, Hau DKP, Wong WY, Lam KH, Bian ZX, Lee KKH, Chui CH (2015b) Evaluation of berberine/bovine serum albumin nanoparticles for liver fibrosis therapy. Green Chem 17:1640–1646

Leonard NMW, Laura C, Mohan Ram S (2002) Applications of bismuth(III) com‑pounds in organic synthesis. Tetrahedron 58(42):8373–8397

Magesh CJ, Magesh SV, Perumal PT (2004) Highly diastereoselective inverse electron demand (IED) Diels–Alder reaction mediated by chiral salen‑AlCl complex: the first, target‑oriented synthesis of pyranoquinolines as potential antibacterial agents. Bioorg Med Chem Lett 14:2035–2040

Mohan R (2010) Green bismuth. Nat Chem 2(4):336Ollevier T (2013) New trends in bismuth‑catalyzed synthetic transformations.

Org Biomol Chem 11(17):2740–2755Priestley ES, De Lucca I, Zhou J, Zhou J, Saiah E, Stanton R, Robinson L, Luett‑

gen JM, Wei A, Wen X, Knabb RM, Wong PC, Wexler RR (2013) Discovery and gram‑scale synthesis of BMS‑593214, a potent, selective FVIIa inhibi‑tor. Bioorg Med Chem Lett 23:2432–2435

Schelenz S, Abdallah S, Gray G, Stubbings H, Gow I, Baker P, Hunter PR (2011) Epidemiology of oral yeast colonization and infection in patients with hematological malignancies, head neck and solid tumors. J Oral Pathol Med 40:83–89

Subramanian S, Kim NS, Thanigaimalai P, Sharma VK, Lee KC, Kang JS, Kim HM, Jung SH (2011) Structure–activity relationship studies of novel arylsulfonylimidazolidinones for their anticancer activity. Eur J Med Chem 46:3258–3264

Vargas Méndez LY, Zacchino SA, Kouznetsov VV (2010) Synthesis of new 4‑methyl‑2‑(4‑pyridyl)‑1,2,3,4‑tetrahydroquinolines as potent antifungal compounds. J Braz Chem Soc 21:105–111

Witherup KMR, Richard W, Graham AC, Bernard AM, Salvatore MJ, Lumma WC, Anderson PS, Pitzenberger SM, Varga SL (1995) Martinelline and martinellic acid, novel G‑protein linked receptor antagonists from the tropical plant Martinella iquitosensis (bignoniaceae). J Am Chem Soc 117:6682–6684

Zuntini AR, Lohmann LG (2014) Synopsis of Martinella Baill. (Bignonieae, Bignoniaceae), with the description of a new species from the Atlantic Forest of Brazil. PhytoKeys 37:15–24